WJV  Vol.4 No.3 , August 2014
Distinct Cytokine Profiles in Patients with Oligoarticular Juvenile Idiopathic Arthritis after in Vitro Blockade of T Cells by Cyclosporine and Abatacept
Abstract: Oligoarticular juvenile idiopathic arthritis (oJIA) is an antigen-driven and lymphocyte-mediated disorder affecting the adaptive immune system. Auto reactive T cells produce pro-inflammatory cytokines as IFN-γ and IL-17. Failure of regulatory T cells leads to decreased production of anti-inflammatory IL-10 and results in the loss of immune tolerance. Therapeutic strategies suppress T cell dependent immune responses and consequently inhibit the process of inflammation. The aim of the study was to investigate the effect of T cell suppression on the cytokine network in oJIA patients. Therefore we examined the cytokine concentration after in vitro inhibition of T cells by cyclosporine and abatacept in patients with persistent oJIA and healthy control subjects. This single center cohort study consisted of oJIA affected children and control subjects. Cytokine profiles from cell culture supernatants were examined with multiplex fluorescent bead immunoassay by flow cytometry. High amounts of IL-17 were only observed in the collective of oJIA patients after T cell stimulation. Cyclosporine suppresses its concentration effectively. IL-2 and IFN-γ are present in both groups. We found IL-6 and TNF-α in high concentrations after T cell activation. While TNF-α concentration is suppressed by both drugs, IL-6 concentration remains high in oJIA patients. Concentrations of IL-4 and IL-10 were not found to be influenced in status of activation or suppression. In conclusion, the results of the present study imply that IL-17 is the crucial T cell cytokine in oligoarticular JIA. Only cyclosporine could inhibit the secretion of IL-17 effectively. IL-2 and IFN-γ are not specific for oligoarticular JIA. Both cytokines are found as well in healthy control subjects after T cell stimulation. Relevant pro-inflammatory macrophage cytokines in oligoarticular JIA are TNF-α and IL-6. T cell suppression by cyclosporine and abatacept inhibits TNF-α but not IL-6 effectively. Production of anti-inflammatory cytokines is not influenced by T cell suppression.
Cite this paper: Strothmann, L. , Kirchner, M. , Sonnenschein, A. and Mannhardt-Laakmann, W. (2014) Distinct Cytokine Profiles in Patients with Oligoarticular Juvenile Idiopathic Arthritis after in Vitro Blockade of T Cells by Cyclosporine and Abatacept. World Journal of Vaccines, 4, 133-146. doi: 10.4236/wjv.2014.43016.

[1]   Ravelli, A. and Martini, A. (2007) Juvenile Idiopathic Arthritis. The Lancet, 369, 767-778.

[2]   Petty, R.E., Southwood, T.R., Manners, P., Baum, J., Glass, D.N., Goldenberg, J., et al. (2004) International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis: Second Revision, Edmonton, 2001. The Journal of Rheumatology, 31, 390-392.

[3]   Macaubas, C., Nguyen, K., Milojevic, D., Park, J.L. and Mellins, E.D. (2009) Oligoarticular and Polyarticular JIA: Epidemiology and Pathogenesis. Nature Reviews Rheumatology, 5, 616-626.

[4]   Kamphuis, S., Hrafnkelsdóttir, K., Klein, M.R., de Jager, W., Haverkamp, M.H., van Bilsen, J.H.M., et al. (2006) Novel Self-Epitopes Derived from Aggrecan, Fibrillin, and Matrix Metalloproteinase-3 Drive Distinct Autoreactive T-Cell Responses in Juvenile Idiopathic Arthritis and in Health. Arthritis Research & Therapy, 8, R178.

[5]   Massa, M., Mazzoli, F., Pignatti, P., De Benedetti, F., Passalia, M., Viola, S., et al. (2002) Proinflammatory Responses to Self HLA Epitopes Are Triggered by Molecular Mimicry to Epstein-Barr Virus Proteins in Oligoarticular Juvenile Idiopathic Arthritis. Arthritis and Rheumatism, 46, 2721-2729.

[6]   Visvanath, V., Myles, A., Dayal, R. and Aggarwal, A. (2011) Levels of Serum Matrix Metalloproteinase-3 Correlate with Disease Activity in the Enthesitis-related Arthritis Category of Juvenile Idiopathic Arthritis. The Journal of Rheumatology, 38, 2482-2487.

[7]   Gattorno, M., et al. (2002) Synovial Membrane Expression of Matrix Metalloproteinases and Tissue Inhibitor 1 in Juvenile Idiopathic Arthritides. The Journal of Rheumatology, 29, 1774-1779.

[8]   Nistala, K., Moncrieffe, H., Newton, K.R., Varsani, H., Hunter, P. and Wedderburn, L.R. (2008) Interleukin-17-Producing T Cells Are Enriched in the Joints of Children with Arthritis, but Have a Reciprocal Relationship to Regulatory T Cell Numbers. Arthritis and Rheumatism, 58, 875-887.

[9]   Honorati, M.C., Meliconi, R., Pulsatelli, L., Canè, S., Frizziero, L. and Facchini, A. (2001) High in Vivo Expression of Interleukin-17 Receptor in Synovial Endothelial Cells and Chondrocytes from Arthritis Patients. Rheumatology, 40, 522-527.

[10]   Zrioual, S., Toh, M.-L., Tournadre, A., Zhou, Y., Cazalis, M.-A., Pachot, A., et al. (2008) IL-17RA and IL-17RC Receptors Are Essential for IL-17A-Induced ELR+ CXC Chemokine Expression in Synoviocytes and Are Overexpressed in Rheumatoid Blood. Journal of Immunology, 180, 655-663.

[11]   van Bezooijen, R.L., van der Wee-Pals, L., Papapoulos, S.E. and Lowik, C.W.G.M. (2002) Interleukin 17 Synergises with Tumour Necrosis Factor α to Induce Cartilage Destruction in Vitro. Annals of the Rheumatic Diseases, 61, 870-876.

[12]   Koshy, P.J., Henderson, N., Logan, C., Life, P.F., Cawston, T.E. and Rowan, A.D. (2002) Interleukin 17 Induces Cartilage Collagen Breakdown: Novel Synergistic Effects in Combination with Proinflammatory Cytokines. Annals of the Rheumatic Diseases, 61, 704-713.

[13]   van den Berg, W.B., van Lent, P.L., Joosten, L.A.B., Abdollahi-Roodsaz, S. and Koenders, M.I. (2007) Amplifying Elements of Arthritis and Joint Destruction. Annals of the Rheumatic Diseases, 66, iii45-iii48.

[14]   Koenders, M.I., Lubberts, E., van de Loo, F.A., Oppers-Walgreen, B., van den Bersselaar, L., Helsen, M.M., et al. (2006) Interleukin-17 Acts Independently of TNF-Alpha under Arthritic Conditions. Journal of Immunology, 176, 6262-6269.

[15]   Langier, S., Sade, K. and Kivity, S. (2010) Regulatory T Cells: The Suppressor Arm of the Immune System. Autoimmunity Reviews, 10, 112-115.

[16]   Cao, D., van Vollenhoven, R., Klareskog, L., Trollmo, C. and Malmstrom, V. (2004) CD25brightCD4+ Regulatory T Cells Are Enriched in Inflamed Joints of Patients with Chronic Rheumatic Disease. Arthritis Research & Therapy, 6, R335-R346.

[17]   de Kleer, I.M., Wedderburn, L.R., Taams, L.S., Patel, A., Varsani, H., Klein, M., de Jager, W., Pugayung, G., Giannoni, F., Rijkers, G., Albani, S., Kuis, W. and Prakken, B. (2004) CD4+CD25bright Regulatory T Cells Actively Regulate Inflammation in the Joints of Patients with the Remitting Form of Juvenile Idiopathic Arthritis. Journal of Immunology, 172, 6435-6443.

[18]   Sakaguchi, S., Yamaguchi, T., Nomura, T. and Ono, M. (2008) Regulatory T Cells and Immune Tolerance. Cell, 133, 775-787.

[19]   Horwitz, D.A., Zheng, S.G. and Gray, J.D. (2008) Natural and TGF-Beta-Induced Foxp3+CD4+ CD25+ Regulatory T Cells Are Not Mirror Images of Each Other. Trends in Immunology, 29, 429-435.

[20]   Lin, Y.T., Wang, C.T., Gershwin, M.E. and Chiang, B.L. (2011) The Pathogenesis of Oligoarticular/Polyarticular vs Systemic Juvenile Idiopathic Arthritis. Autoimmunity Reviews, 10, 482-489.

[21]   Cascao, R., Rosario, H.S., Souto-Carneiro, M.M. and Fonseca, J.E. (2010) Neutrophils in Rheumatoid Arthritis: More than Simple Final Effectors. Autoimmunity Reviews, 9, 531-535.

[22]   Reem, G.H., Cook, L.A. and Vilcek, J. (1983) Gamma Interferon Synthesis by Human Thymocytes and T Lymphocytes Inhibited by Cyclosporin A. Science, 221, 63-65.

[23]   Schreiber, S.L. and Crabtree, G.R. (1992) The Mechanism of Action of Cyclosporin A and FK506. Immunology Today, 13, 136-142.

[24]   Heinz, C., Heiligenhaus, A., Kummerle-Deschner, J. and Foeldvari, I. (2010) Uveitis in Juvenile Idiopathic Arthritis. Zeitschrift fur Rheumatologie, 69, 411-418.

[25]   Kremer, J.M. (2004) Cytotoxic T-Lymphocyte Antigen 4-Immunoglobulin in Rheumatoid Arthritis. Rheumatic Diseases Clinics of North America, 30, 381-391.

[26]   Ruperto, N., Lovell, D.J., Quartier, P., Paz, E., Rubio-Pérez, N., Silva, C.A., et al. (2008) Abatacept in Children with Juvenile Idiopathic Arthritis: A Randomised, Double-Blind, Placebo-Controlled Withdrawal Trial. Lancet, 372, 383- 391.

[27]   Chi, W., Yang, P.Z., Zhu, X.F., Wang, Y.Q., Chen, L.N., Huang, X.K. and Liu, X.L. (2010) Production of Interleukin-17 in Behcet’s Disease Is Inhibited by Cyclosporin A. Molecular Vision, 16, 880-886.

[28]   Haider, A.S., Lowes, M.A., Suárez-Farinas, M., Zaba, L.C., Cardinale, I., Khatcherian, A., Novitskaya, I., Wittkowski, K.M. and Krueger, J.G. (2008) Identification of Cellular Pathways of “Type 1,” Th17 T Cells, and TNF-and Inducible Nitric Oxide Synthase-Producing Dendritic Cells in Autoimmune Inflammation through Pharmacogenomic Study of Cyclosporine A in Psoriasis. Journal of Immunology, 180, 1913-1920.

[29]   Liu, X., Yang, P.Z., Lin, X.M., Ren, X.R., Zhou, H.Y., Huang, X.K., Chi, W., Kijlstra, A. and Chen, L. (2009) Inhibitory Effect of Cyclosporin A and Corticosteroids on the Production of IFN-Gamma and IL-17 by T Cells in Vogt- Koyanagi-Harada Syndrome. Clinical Immunology, 131, 333-342.

[30]   De Benedetti, F., Robbioni, P., Massa, M., Viola, S., Albani, S. and Martini, A. (1992) Serum Interleukin-6 Levels and Joint Involvement in Polyarticular and Pauciarticular Juvenile Chronic Arthritis. Clinical and Experimental Rheumatology, 10, 493-498.

[31]   Lovell, D.J. (2006) Update on Treatment of Arthritis in Children: New Treatments, New Goals. Bulletin of the NYU Hospital for Joint Diseases, 64, 72-76.

[32]   Otten, M.H., Prince, F.H.M., Anink, J., ten Cate, R., Hoppenreijs, E.P.A.H., Armbrust, W., et al. (2013) Effectiveness and Safety of a Second and Third Biological Agent after Failing Etanercept in Juvenile Idiopathic Arthritis: Results from the Dutch National ABC Register. Annals of the Rheumatic Diseases, 72, 721-727.

[33]   Brunner, H.I., Ruperto, N., Zuber, Z., Keane, C., Harari, O., Kenwright, A., et al. (2014) Efficacy and Safety of Tocilizumab in Patients with Polyarticular-Course Juvenile Idiopathic Arthritis: Results from a Phase 3, Randomised, Double-Blind Withdrawal Trial. Annals of the Rheumatic Diseases.

[34]   de Jager, W., Hoppenreijs, E.P.A.H., Wulffraat, N.M., Wedderburn, L.R., Kuis, W. and Prakken, B.J. (2007) Blood and Synovial Fluid Cytokine Signatures in Patients with Juvenile Idiopathic Arthritis: A Cross-Sectional Study. Annals of the Rheumatic Diseases, 66, 589-598.

[35]   Mangge, H., Kenzian, H., Gallistl, S., Neuwirth, G., Liebmann, P., Kaulfersch, W., Beaufort, F., Muntean, W. and Schauenstein, K. (1995) Serum Cytokines in Juvenile Rheumatoid Arthritis. Correlation with Conventional Inflammation Parameters and Clinical Subtypes. Arthritis and Rheumatism, 38, 211-220.